Chronic alcohol consumption leads to alterations in the contractile function of the heart and alcoholism is a leading cause of cardiomyopathy. Alcohol also depresses heart function through a direct interaction with the cardiac muscle cells during acute exposure and it is likely that adaptive responses to these acute effects contribute to the etiology of alcoholic heart disease. A number of targets for the acute effects of alcohol have been identified and several of these impact on the pathway of excitation-contraction coupling (E-C coupling). However, the mechanisms underlying the chronic effects of alcohol on the heart remain obscure. In this study we will investigate the mechanisms responsible for the acute and chronic actions of alcohol in isolated ventricular muscle cells obtained from the hearts of rats maintained on an alcohol feeding protocol for prolonged periods, and in control animals. We will determine how the acute effects of alcohol on individual elements of the E-C coupling cascade are integrated to give rise to the depression of contractility. In the context of the chronic effects of alcohol, we have recently identified a potentially important lesion in the regulation of cardiac E-C coupling. Specifically, the activation of the rate of rise and amplitude of the [Ca2+]i transients by beta-adrenergic agonists is greatly decreased in alcohol-fed rats. By contrast, the beta-adrenergic stimulation of the relaxation phase is unaffected. This defect appears to be distal to beta- adrenergic receptor activation and cAMP formation. However, the L-type voltage-dependent Ca2+ channels of these "alcoholic" cardiomyocytes give reduced currents compared to their paired controls, and are largely resistant to activation by isoproterenol. This loss of Ca2+ channel activity is associated with an increased density of Ca2+ channel alpha1 subunit measured as dihydropyridine binding. We will investigate the mechanism of this novel effect and examine the role of the altered Ca2+ channel properties in the contractile dysfunction of these cells. We hypothesize that chronic alcohol consumption modifies the expression level and subunit composition of the Ca2+ channels. Such a defect could contribute to the depression of contractility and may be a precipitating factor in the development of other aberrant adaptive processes m the heart that eventually lead to cardiac failure. These studies will be carried out using molecular and cellular physiology approaches to study the mechanisms and components of cardiac muscle E-C coupling in cardiomyocytes from control and alcohol-fed rats.